Alzheimer's disease is a devastating eurodegenerative disorder affecting more than 5 million older people in the U.S.A. for which there is not treatment. It is imperative to define the earliest cellular, mechanisms that drive the earliest onset of dementia in order to develop novel disease modifying therapeutic approaches. The thrust of this PPG entitled Neurobiology of Mild Cognitive Impairment in the Elderly continues to be to elucidate the cellular and molecular basis or chain of events leading from no cognitive impairment (NCI) to mild cognitive impairment (MCI), the time-point considered the most likely therapeutic window. Moreover, we will refocus our efforts to include NCI subjects with pathology suggestive of AD, in order to resolve the neuropathogenic sequela underlying preclinical AD. We will implement a series of interrelated circuit-based projects centered on the cholinergic basal forebrain cortical (CBF) projection system, which displays early cellular pathology prior to MCI (preclinical AD), plays a pivotal role in the onset of clinical dementia and is the basis for most of the current FDA approved drugs for AD. The investigations proposed for this competitive renewal application of the Program Project brings together a number of basic and clinician scientists from Chicago and outside universities to investigate circuit based neuronal system dysfunction at a very early stage in the disease progress termed preclinical AD compared to prodromal AD (mild cognitive impairment). The Program Project consists of an Administrative Core with a Clinical/Tissue Distribution component and a Statistics and Data Management Core. In addition the following four research projects complete the program: 1) Tau abnormalities and Mild Cognitive Impairment in the Elderly (Lester Skip Binder, Northwestern University Medical School); 2) Age-Related Neuropathology and Mild Cognitive Impairment in the Elderly (James Lah, Emory University School of Medicine); 3) Cholinergic Basal Forebrain Neurotrophic Abnormalities and Mild Cognitive Impairment in the Elderly (Elliott Mufson, Rush Medical Center); and Synaptic Abnormalities and Mild Cognitive Impairment in the Elderly (Milos Ikonomovic, University of Pittsburgh). Each core supports all research projects and all projects interact.